Hyperglycemia and insulin resistance are common in many metabolic disorders such Type 2 diabetes, obesity, and metabolic syndrome. In these chronic conditions, there is a decreased responsiveness to endogenous insulin (insulin resistance). The decreased responsiveness to insulin results in a reduction in insulin-regulated glucose disposal, which occurs mostly in skeletal muscle. Acute insulin resistance and hyperglycemia are much less studied, but are characteristic metabolic responses to infections and injuries such as surgery, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of ICU patients may reduce both morbidity and mortality associated with critical illness. However, there is some controversy concerning the proper use of intensive insulin therapy, and under what conditions it can do the most good, or conversely when it is unnecessary or harmful. The increased incidence of hypoglycemic incidents is a major complication of intensive insulin therapy. Even though intensive insulin therapy is now extensively used in the ICU, little is known about the mechanisms underlying the acute onset of insulin resistance. For instance, how quickly it develops, what are the causative factors, what intracellular signaling pathways are affected, and what tissues are involved. An understanding of how this insulin resistance develops will be important in determining the proper application of intensive insulin therapy, the most advantageous time for initiation following different injuries, and may suggest new treatment protocols to increase survival of critically ill patients. For instance, is therapy to reduce insulin resistance more advantageous to the patient than intensive insulin therapy? And what tissue or tissues need to be targeted? Our recently published and preliminary data indicate that there are insulin receptor and post-receptor defects in insulin signaling that develop in skeletal muscle following surgical trauma and hemorrhage. The data suggests an important role for the glucocorticoids and proinflammatory cytokines, but how they interact to cause the the initial development of insulin resistance is unknown. Additional preliminary date indicate that the mechanisms of the development of insulin resistance are different in the three main insulin target tissues, skeletal muscle, liver, and adipose tissue. This makes it necessary to study each tissue separately, to determine how this insulin resistance occurs. However, this has a possible advantage of eventually being able to specifically target individual tissues, with treatments less likely than intensive insulin therapy to cause hypoglycemic incidents. In addition, understanding the development of insulin resistance may be important in determining the proper application of intensive insulin therapy, and under what conditions this therapy might do the most good. PUBLIC HEALTH RELEVANCE: Risk factors for many chronic and critical illnesses, which often require surgical intervention, are increased in the VA population. For example type 2 diabetes has a prevalence that approaches 10% in the US, but afflicts 15-20% of outpatients in the VA population, contributing to vascular disease which can result in an increased need for cardiovascular surgery and peripheral amputations. Skeletal muscle plays a central role in whole-body glucose metabolism. The proposed studies are vital to understand the role of skeletal muscle in the acute development of insulin resistance following injuries and infections. If we can understand how acute insulin resistance develops, and the causative factors can be determined, it may be possible to treat the metabolic derangements following injuries to specifically correct the abnormalities and decrease patient morbidity and mortality.